The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury

• Main Authors: Rajpal Sharad, Miranpuri Gurwattan, Allcock Bradley, Tilghman Jessica, Cain John, Baggott Christopher, Cramer Samuel W, Sun Dandan, Resnick Daniel
• Format: Article
• Language: English
• Published: SAGE Publishing 2008-09-01
• Series: Molecular Pain
• Online Access: http://www.molecularpain.com/content/4/1/36

<p>Abstract</p> <p>Background</p> <p>Altered Cl^-homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl^-regulatory proteins, Na⁺-K⁺-Cl^-cotransporter 1 (NKCC1) and K⁺-Cl^-cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI).</p> <p>Results</p> <p>Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30 mg/kg, i.p.) in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p < 0.05). The group administered with the vehicle alone showed no anti-hyperalgesic effects. Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2–14 post-SCI and peaked on day 14 post-SCI (p < 0.05). Concurrently, a down-regulation of KCC2 protein was detected during day 2–14 post-SCI. The rats with TH exhibited a sustained loss of KCC2 protein during post-SCI days 21–42. No significant changes of these proteins were detected in the rostral region of the spinal cord.</p> <p>Conclusion</p> <p>Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI. The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.</p>